Overuse of antibiotics and the associated increase in bacterial resistance is impacting the efficacy of antibiotics in the treatment of wound infection. Effective alternatives to antibiotics are thus desirable.
Topical antimicrobial materials, and preparations containing them, have long been recognized as playing an important part in minimizing the opportunity for skin and wound infections. Antiseptics are non-selective chemical agents that can be safe to use on living tissue. Molecular iodine, ionic silver and oxidizing agents, such as sodium hypochlorite and chlorine dioxide, have been recognized as antiseptic agents with effectiveness against a wide range of microorganisms. There are, however, several barriers to making an effective antimicrobial composition for application to wounds based on such agents. One problem is that these antiseptic agents tend to react with organic materials found in the wound other than the intended microbial targets. This means that to be effective, antiseptic agents need to be included in treatment compositions at high levels, which may cause undesirable side effects with prolonged use such as cell toxicity, hypersensitivity reactions, skin staining and systemic effects. Such side effects are further described in “In vitro cytotoxity of silver: implication for clinical wound care”. Poon V K, Burd A. Burns. 2004 March; 30(2):140-7, “A review of iodine toxicity reports”. Pennington J A. J Am Diet Assoc. 1990 November; 90(11):1571-81 and “Topical antimicrobial toxicity”. Lineaweaver W, Howard R, Soucy D, McMorris S, Freeman J, Crain C, Robertson J, Rumley T. Arch Surg. 1985 March; 120(3):267-70.
Wounds are often colonized by a variety of microorganisms, some of which may cause infection. It is increasingly recognized that microbial populations living within a biofilm environment contribute to delayed healing and infection. Biofilms are comprised of exopolymeric substances that are produced by bacteria once the bacteria attach to a surface, and this helps to protect microorganisms from immune cells and antimicrobial agents. Since efficacy of antimicrobial agents (e.g., antibiotics and antiseptics) is compromised by the biofilm matrix, strategies to disrupt the biofilm and expose microorganisms within can be helpful in increasing the activity level of antimicrobial agents and thus reduce the concentration of such agents needed to make an effective composition.
Ethylenediaminetetra-acetic acid (EDTA) added as the di-sodium or calcium di-sodium salts has been used to treat topical infections or to treat hard surfaces such as catheters. WO03/047341 describes the use of EDTA, for example, as an additive for a toothpaste. EDTA is also used as a formulation agent to reduce the effects of water hardness and, generally, as a chelating agent.
EDTA has been described in combination with other antibiotic agents. For example, in U.S. Pat. No. 5,998,488, EDTA is used in combination with an antimicrobial preservative in a solution for ophthalmic use. Formulations suitable for topical use on wounds have not been proposed.
There is, thus, a need for a composition which has the benefits of an antimicrobial agent but which reduces the potential of adverse reactions. Surprisingly, we have found that EDTA is capable of disrupting biofilms by chelating the metal ions, calcium and magnesium, that maintain the integrity of the biofilm matrix.